EP0419223B1 - Méthode pour caractériser un matériau biologique en condition dynamique par l'utilisation de la spectroscopie dans l'infrarouge proche - Google Patents

Méthode pour caractériser un matériau biologique en condition dynamique par l'utilisation de la spectroscopie dans l'infrarouge proche Download PDF

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EP0419223B1
EP0419223B1 EP90310219A EP90310219A EP0419223B1 EP 0419223 B1 EP0419223 B1 EP 0419223B1 EP 90310219 A EP90310219 A EP 90310219A EP 90310219 A EP90310219 A EP 90310219A EP 0419223 B1 EP0419223 B1 EP 0419223B1
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property
blood
near infrared
spectra
analyzed
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EP0419223A2 (fr
EP0419223A3 (en
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James B. C/O Board Of Regents Of The Callis
David W. C/O Minnesota Mining And Osten
Hatim M. C/O Minnesota Mining And Carim
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University of Washington
3M Co
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University of Washington
Minnesota Mining and Manufacturing Co
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/145—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue
    • A61B5/14535—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue for measuring haematocrit
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/145—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue
    • A61B5/1455—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue using optical sensors, e.g. spectral photometrical oximeters
    • A61B5/14551—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue using optical sensors, e.g. spectral photometrical oximeters for measuring blood gases
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/145—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue
    • A61B5/1455—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue using optical sensors, e.g. spectral photometrical oximeters
    • A61B5/14551—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue using optical sensors, e.g. spectral photometrical oximeters for measuring blood gases
    • A61B5/14557—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue using optical sensors, e.g. spectral photometrical oximeters for measuring blood gases specially adapted to extracorporeal circuits
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/72—Signal processing specially adapted for physiological signals or for diagnostic purposes
    • A61B5/7235—Details of waveform analysis
    • A61B5/7239—Details of waveform analysis using differentiation including higher order derivatives
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/17—Systems in which incident light is modified in accordance with the properties of the material investigated
    • G01N21/25—Colour; Spectral properties, i.e. comparison of effect of material on the light at two or more different wavelengths or wavelength bands
    • G01N21/31—Investigating relative effect of material at wavelengths characteristic of specific elements or molecules, e.g. atomic absorption spectrometry
    • G01N21/35—Investigating relative effect of material at wavelengths characteristic of specific elements or molecules, e.g. atomic absorption spectrometry using infrared light
    • G01N21/359—Investigating relative effect of material at wavelengths characteristic of specific elements or molecules, e.g. atomic absorption spectrometry using infrared light using near infrared light
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2201/00—Features of devices classified in G01N21/00
    • G01N2201/12—Circuits of general importance; Signal processing
    • G01N2201/129—Using chemometrical methods

Definitions

  • the present invention relates to the analysis of a sample of matter of biological origin in a dynamic condition using the near-infrared (NIR) spectrum of that biological matter having a water content.
  • NIR near-infrared
  • the method permits prediction of a property of interest because the biological matter may be approximated to contain two compartments where one compartment has a proportionally larger or smaller amount of water than the other compartment having the property of interest.
  • Analysis of an unknown sample in a dynamic condition is achieved by use of mathematical techniques developed using a NIR spectral training set of known samples and independent quantification of the property of interest in the known samples in that training set.
  • Presence of water in an organism is the common denominator of life.
  • the corpus of an organism is compartmentalized with each compartment capable of being distinguished by the amount of water it contains.
  • the processes of osmosis and reverse osmosis in an organism act to stabilize this compartmentalization.
  • Determination of the volume fraction or percentage concentration of components other than water in the various compartments of biological matter, such as tissue or blood, is often critical to the determination of the well-being or homeostasis of the organism.
  • biological matter such as tissue or blood
  • the diagnosis of such biological matter provides an excellent medium to assess the homeostatic condition of the organism.
  • Hematocrit is the volume fraction of agglomerated erythrocytes in whole blood.
  • Hemoglobin is the chemical molecule in the erythrocytes which transports oxygen to the cells. Hemoglobin may take several forms depending on the presence or absence of oxygen or other chemicals which may be bonded to active sites in the hemoglobin molecule. Hematocrit in whole blood has been found to have a suitable direct mathematical correlation to the concentration of hemoglobin, providing the blood has few or no lysed erythrocytes.
  • US-A-4 651 741 discloses a method of determining the blood oxygen saturation by measurement of the absorption of the sample in the red and infra red and using the ratio of these measurements and calibration constants in an equation to calculate the saturation of oxygen.
  • the calibration constants are hematocrit dependent and their values as a function thereof are contained in a look up table and are selected for the hematocrit level to be measured.
  • Water is omnipresent in whole blood. Hemoglobin is dissolved in the erythrocytes, while plasma is principally water. But the amount of water in which hemoglobin is dissolved, and hence in erythroctyes, is comparatively less than the amount of water in the plasma.
  • Clinical analysis of an organism requires monitoring of the status of or the changes in condition. As a result of injury or illness or other deleterious biological conditions, the hematocrit or the concentration of hemoglobin in erythrocytes available for oxygen transport to the cells of the organism may be diminished below healthy levels even to the point of critical life sustaining levels. Also, analysis of various types of anemia is vital to continuing successful treatment of a patient, especially in critical care facilities such as emergency rooms, operating rooms, or intensive care units, including neo-natal units. Less traumatic but just as vital, most blood donors must undergo hematocrit testing to assure that their blood to be donated has appropriate hemoglobin levels for later use.
  • Hemoglobin concentrations are measured traditionally using lengthy and complicated procedures which require the preconditioning, i.e., chemical modification or component separation, of a blood sample withdrawn from the body.
  • the traditional methods destroy the blood, preventing its return to the body.
  • hemoglobin One popular method for the determination of hemoglobin involves (1) lysing the red blood cells by hypotonic shock or sonification, (2) removal of the red blood cell membranes to produce a clear solution, (3) addition of a cyanide ion reagent to normalize or convert the various forms of hemoglobin to a single form hemoglobin (e.g., cyanomet hemoglobin), and (4) spectrophotometric analysis to derive the hemoglobin concentration of the normalized sample.
  • a cyanide ion reagent to normalize or convert the various forms of hemoglobin to a single form hemoglobin (e.g., cyanomet hemoglobin)
  • spectrophotometric analysis to derive the hemoglobin concentration of the normalized sample.
  • centrifugal attribution in a test tube of specific diameter centrifugal attribution in a test tube of specific diameter and Coulter counting.
  • Centrifugal attribution involves centrifuging of blood withdrawn from the body in a tube of specific diameter at pre-selected centrifugal forces and times that serve to separate the blood into two portions.
  • the heavier portion is the agglomeration of erythrocytes in the whole blood.
  • the lighter portion is plasma dominated by water.
  • the ratio of the volume of the erthrocytes to the total volume of the blood sample in the centrifuge tube is the hematocrit.
  • Coulter counting determines hematocrit by physical counting of red blood cells and a determination, through the size of each cell on a cell-by-cell basis, the volume of each. After a predetermined number of blood cells are counted, the hematocrit is determined by the number of red blood cells counted multiplied by the mean volume of the blood cells for a given blood sample.
  • U.S. Patent 4,243,883 describes a monitor of a flowing stream of blood using a discrete near-infrared wavelength.
  • U.S. Patent 4,745,279 describes a dual path NIR spectral analysis at discrete wavelengths of flowing whole blood.
  • U.S. Patent 4,805,623 describes a NIR spectral method and apparatus using multiple wavelengths to determine the concentration of a dilute component of known identity in comparison with a reference component of known concentration.
  • the near-infrared (NIR) spectral region of electromagnetic radiation contains absorbance peaks for the various forms of hemoglobin and water.
  • NIR near-infrared
  • Prior spectral analytical efforts have focused on the measurement of the diffuse transmission or reflectance of near infrared light through blood samples.
  • light scattering in the samples and other properties which interfere with accurate measurement cause variances in the specific spectrum taken.
  • even using measurements taken with sensitive instrumentation is not satisfactory.
  • the choice of specific wavelengths in near-infrared spectra for which whole blood samples may be best monitored is not straightforward due to variances in the broad peaks of water and various forms of hemoglobin in such NIR spectra.
  • the present invention provides a method for rapidly, inexpensively, and accurately characterizing the properties of matter of biological origin containing water by analyzing the near-infrared spectrum of the biological matter while in a dynamic condition using techniques useful with NIR spectral instrumentation and predicting the properties without sample preconditioning.
  • the techniques seek to minimize the effect of light scattering and use mathematical regression analysis to permit transforming the observed spectrum into a prediction of the property to be analyzed.
  • the method of the present invention avoids chemical alteration or physical separation of the components in the sample of biological matter.
  • the method also avoids inaccuracies caused by irrelevant variations in samples and instrumental noise in measurement techniques.
  • the method of the present invention is founded on the principle that the biological matter may be considered to consist of essentially two compartments: one compartment which has a proportionally different (larger or smaller) amount of water than the other compartment related to or having the property to be analyzed.
  • the present invention is also founded on the principle that identification of the volume or weight fraction or concentration of water in the biological matter will serve as the basis for calculation of the property to be analyzed.
  • the method of the present invention is further founded on the principle that the establishment of a training set of the combination of NIR spectra of several samples of the biological matter and the independent quantification of the property to be analyzed in each sample provides a source of mathematical comparison for accurately predicting the property to be analyzed in an unknown additional sample by using such mathematical comparison.
  • hematocrit or hemoglobin concentration is achieved by obtaining near-infrared spectra of a statistically sufficient number of samples of whole blood to establish a training set for mathematical comparisons against individual additional unknown samples of other whole blood.
  • the property to be analyzed in the whole blood e.g., hematocrit or hemoglobin concentration
  • hematocrit or hemoglobin concentration is independently quantified by using an independent known technique: lysing and chemical alteration for hemoglobin and Coulter counting or centrifuging for hematocrit.
  • the nature of the inter-relationship between the hematocrit or hemoglobin and the water content is statistically correlated to establish the source of comparison when predicting unknown samples.
  • a pre-processing technique is employed.
  • One useful pre-processing technique is disclosed in European Patent Publication 0 476 192 based on an application claiming priority from U.S. Patent Application Serial Number 07/408,747. That technique is a multiple derivative transformation of the training set spectra and the unknown sample's spectrum to minimize the effect of light scattering and other instrumental noise on the various spectra, in order to allow a mathematical correlation using the multiple derivative of the spectral intensity at a single wavelength to accurately predict the property of the compartment being analyzed in the unknown sample.
  • a different and useful type of pre-processing technique is disclosed in European Patent Publication 0 419 222 based on an application claiming priority from U.S. Patent Application Serial Number 07/408,746. That technique is a ratio pre-processing technique which applies a ratio of an absorbance peak of the water content in the biological matter to another absorbance measuring point in order to minimize variations due to sampling techniques and instrumentation factors. This allows the accurate mathematical correlation to predict the property of the compartment being analyzed in the unknown sample.
  • the absorbance peak of water in this region is primarily the result of simultaneous excitation of the symmetric O-H stretch, the O-H bending mode, and the antisymmetric O-H stretch of the water molecule, whether existing in the biological matter as free water, bound to other molecules, or other forms.
  • the peak of absorbance of water in the 1150-1190 nm range may be largely isolated from the absorbance of hemoglobin, it is not totally isolated. Indeed, it is preferred in the present invention to distinguish between the two principal forms of the hemoglobin component in whole blood, oxyhemoglobin and deoxyhemoglobin, and add that independent variable to the regression analysis which both establishes the training set and predicts the unknown sample's hematocrit or hemoglobin concentration.
  • Gathering the training set spectral data for the samples of the biological matter depends on the type of instrumentation to be employed.
  • the biological matter is diverted from the body of the organism and returned.
  • One embodiment of diversion and return of the biological matter to the patient is an extracorporeal loop described herein.
  • Gathering the unknown sample spectral data for analysis also depends on the type of instrumentation to be employed.
  • the unknown sample may be diverted from the body of the organism for spectral detection or measurement and returned to the body, or the unknown sample may be analyzed in vivo.
  • One embodiment of diversion and return of the biological matter to the patient is the extracorporeal loop described herein.
  • Processing and instrumentation variabilities are dependent upon the method by which the training set is established and the method by which the unknown samples are analyzed.
  • the biological fluid is moving when being spectrally analyzed, a dynamic condition.
  • the whole blood is spectrally analyzed in a dynamic condition either using diffuse transmission detection or reflectance detection as appropriate.
  • the NIR spectrum of the unknown sample is obtained from either continuous or discrete wavelength measuring instrumentation. After the spectrum is obtained and subjected to the appropriate pre-processing, the property of interest may be predicted by a mathematical correlation to the training set spectra.
  • FIG. 1 is a schematic block diagram of the instrumentation useful in a method carried out in accordance with the present invention.
  • FIG. 2 is a schematic flow chart of the methods to mathematically minimize variability of spectral data using multiple derivative transformation techniques and establish the mathematical correlation between known samples and the training set spectra, in order to permit the predicting of the property of interest in an unknown sample by comparison with the mathematical correlation.
  • FIG. 3 is a schematic flow chart of the methods to mathematically minimize variability of spectral data using ratioing techniques and establish the mathematical correlation between known samples and the training set spectra, in order to permit the predicting of the property of interest in an unknown sample by comparison with the mathematical correlation.
  • FIG. 4 is a graphic representation of typical whole blood spectra detected in a dynamic condition indicating the effects of typical light scattering variances and other instrumental noise variances.
  • FIG. 5 is a graphic representation of the same whole blood spectra as in FIG. 4 after the application of the multiple derivative transformation to minimize the effects of typical light scattering variances and other instrumental noise variances.
  • FIG. 6 is a correlation plot of correlation coefficient versus wavelength for hemoglobin after the spectral data were second derivative pre-processed and regression analysis of the spectral data was performed against hemoglobin.
  • FIG. 7 is a correlation map of correlation cofficient squared versus wavelength for hemoglobin after ratio pre-processing and regression analysis of the spectral data was performed against hemoglobin.
  • FIG. 8 is a graph showing the accuracy of prediction of hematocrit after multiple derivative transformation pre-processing compared with actual hematocrit values determined by prior art methods.
  • FIG. 9 is a graph showing the accuracy of prediction of hematocrit after ratioing pre-processing compared with actual hematocrit values determined by prior art methods.
  • FIG. 10 is a schematic flow chart, similar to FIG. 2, of another method of the present invention to mathematically minimize variability of spectral data using multiple derivative transformation techniques and adjustment for the different forms of hemoglobin.
  • FIG. 11 is a schematic flow chart, similar to FIG. 2, of another method of the present invention to mathematically minimize variability of spectral data using ratioing techniques and adjustment for the different forms of hemoglobin in the whole blood.
  • FIG. 12 is a graph showing the accuracy of prediction of hematocrit after multiple derivative transformation pre-processing and adjusting for the different forms of hemoglobin present in the whole blood, compared with actual hematocrit values determined by prior art methods.
  • FIG. 13 is a graph showing the accuracy of prediction of hematocrit after ratioing pre-processing and adjusting for the different forms of hemoglobin present in the whole blood, compared with actual hematocrit values determined by prior art methods.
  • FIG. 14 is a schematic depiction of the components of the extracorporeal blood loop of the present invention.
  • One embodiment of the present invention is the analysis of hematocrit in whole blood.
  • Another embodiment of the present invention is the analysis of hemoglobin concentration in whole blood.
  • the determination of hematocrit is an excellent correlation to the concentration of hemoglobin in whole blood.
  • one or more methods of independent quantification of the property to be analyzed may be used to provide alternative clinical diagnosis of the condition of the patient.
  • the property of the biological matter to be analyzed must have some correlation either positively or negatively with the water content in order to develop a mathematical correlation therefor in accordance with the present invention. That may not preclude the presence of other components in de minimus volume fractions or concentrations.
  • the presence of white blood cells, platelets, hydrocarbonaceous lipids, and the like are not present in sufficient quantity at the desired level of precision to destroy the validity of the mathematical correlation found.
  • the determination of the oxygen saturation in the whole blood may distinguish between oxyhemoglobin and deoxyhemoglobin, in order to predict the property of interest with greater accuracy.
  • FIG. 1 identifies the schematic block diagram of spectral instrumentation useful in establishing the training set initially and thereafter predicting the property of the compartment to be analyzed in one or more unknown additional samples.
  • FIG. 1 illustrates a typical instrumentation system available which can be used for obtaining the near infrared spectrum of a biological fluid, such as whole blood.
  • FIG. 1 identifies a Model 6250 spectrophotometer manufactured by Near Infrared Systems of Silver Spring, Maryland, formerly known as Model 6250 made by Pacific Scientific.
  • the radiation from a tungsten lamp 100 is concentrated by a reflector 101 and lens 102 on the entrance slit 103 and thereafter passed through an order sorting filter 104 before illuminating a concave holographic grating 105 to disperse the radiation from the tungsten lamp 100 onto the sample 113 in a dynamic condition in an optical blood loop or in the body of the organism.
  • the grating 105 is where the wavelength dispersion occurs.
  • the grating is scanned through the desired wavelength range, typically 680 to 1235 nanometers, by the rotating cam bearing 106, which is coupled to the grating by linkage assembly 107.
  • the selected wavelength passes through exit slit 108 and is guided through the cell 113 through which the sample is moving in direction F, by mirror 109, iris 111, and lenses 110 and 112. After passing through the sample, the remaining radiation is converted to an electrical signal by detector 114.
  • Monochromators such as Model HR 320 available from Instruments S.A. are useful.
  • Polychromators such as the Chemspec Model 100S available from American Holograph or Model JY320 also available from Instruments S.A. may be used to gather the spectral data to establish the training set.
  • Detection means may employ either diffuse transmittance detection devices or reflectance devices available commercially.
  • the Model 6250 spectrophotometer may be configured to detect either diffuse transmittance or diffuse reflectance.
  • the detector 114 may be a silicon detector, a gallium arsenide detector, a lead sulfide detector, an indium gallium arsenide detector, a selenium detector or a germanium detector.
  • Whichever detector is chosen, it is preferred to be consistent in the usage of same detection means for establishing the training set spectra and for measuring the unknown sample's spectrum.
  • polychromatic analyzers using a reversed beam geometry may be used to disperse the transmitted or reflected light into its spectral components and photodiode arrays may be used to detect or measure the dispersed light at different positions along the output spectral plane.
  • the polychromatic analyzer should include an entrance slit that defines the bandwidth of light which is consistent with the spectal resolution desired.
  • One commercially available photodiode array useful with the present invention is Model 1024S photodiode array available from Reticon, Inc., which consists of 1024 diodes of 25 micron width and 2.5 millimeters height. That photodiode array may be used in a complete spectral detection system such as Model ST120 available from Princeton Instruments.
  • interference filters as spectroanalyzers, for example, by passing a series of discrete wavelength interference filters one at a time before a suitable detector. It is also possible to use interferometers or a Hadamard transform spectrometer to analyze the diffuse light.
  • the above detection means are based on detection of spectra from a broad band light source.
  • narrow band sources of NIR light such as tungsten lamps with interference filters, light emitting diodes, or laser (either a single tunable laser or multiple lasers at fixed frequencies)
  • other detection techniques may be used.
  • the input signal can be multiplexed either in time, (to sequence each wavelength), or in wavelength (using sequences of multiple wavelengths), and thereafter modulated and the collected signals demodulated and demultiplexed to provide individual wavelength signals without the need for optical filtering.
  • a computer connected to the instrument to receive the spectral data, perform the analysis described below, and provide a printout or readout of the value of the property predicted.
  • a personal computer such as a "PS/2" Model 50 computer from IBM of Boca Raton, Florida is used and preferred.
  • FIG. 2 is a schematic flow chart of the method of the present invention using for pre-processing the multiple derivative transformation pre-processing technique disclosed in U.S. Patent Application Serial Number 07/408,747, which pre-processing is employed to minimize sample and instrumentation variability.
  • the regression analysis of the method identifies the nature of the mathematical correlation between the property to be analyzed in the first compartment and the water content in the biological matter, in order to predict the property of the compartment to be analyzed in an unknown sample.
  • steps 120 to 128 which comprise the training phase of the analysis
  • steps 129 to 133 which comprise the prediction of the property of an unknown sample.
  • the training or calibration development phase consists of observing a series of blood samples 120 by diverting the samples from one or more animals of the same species through a blood loop or by otherwise observing the samples in the organisms. Additionally, for the independent quantification of property of interest, samples are obtained by withdrawing blood, step 121, from each of the animals participating in step 120.
  • the samples of steps 120 and 121 are analyzed on two parallel paths.
  • the first path consists of independent quantification of the property of interest, step 122. It is important that the independent quantification be done accurately.
  • the accuracy of the method of the present invention is dependent upon the accuracy of the independent quantification step 122 because validation of the mathematical correlation is based on the independently quantified value of the property of interest.
  • the second path consists of irradiating the samples with infrared light and detecting the near infrared spectrum for each sample, step 123, and then computing the second derivative of the spectra, step 124.
  • reference to detecting the near infrared spectrum involves both the measurement of diffusely transmitted or reflected spectrum and the transformation of that spectrum to an absorbance spectrum. The transformation is based on having taken a spectrum of the cell containing only air for calibration purposes.
  • the near infrared spectrum from 680 to 1235 nanometers consists of 700 individual absorbance measurements.
  • the second derivative transformation preprocessing step computes less than the total 700 measurements because some transformations are not available at the edges of the spectra.
  • software such as "Near Infrared Spectral Analysis” commercially available from Pacific Scientific, now known as Near Infrared Systems of Silver Spring, Maryland, one may compute an approximated derivative by using finite difference approximations. Different approximations may yield different derivative spectra and different transformation equations. In such software, different approximations may be adjusted according to segment of the spectrum being measured and the gap between segments being measured.
  • the preprocessed spectra for the set of training samples subjected to second derivative transformation, step 124, are correlated with the values obtained during the independent quantification step 122 by using a mathematical regression technique, step 125, such as linear regression.
  • the second derivative value providing the best correlation of calculated value to actual value is generally the wavelength chosen for the mathematical correlation.
  • One of the outputs of this regression step is a correlation plot, step 126, which graphically shows the wavelengths of the spectrum where the highest correlation is found.
  • the best transformed wavelength in the water band region of 1150 to 1190 nm, step 127, is selected by identifying the peak of optimum correlation.
  • the regression coefficients corresponding to the selected wavelength are saved, step 128, for future application to the analysis of individual samples to predict the property of interest.
  • the steps 129 to 133 in FIG. 2 show the procedure to be followed for predicting hematocrit (abbreviated as HCT in FIG. 2) or hemoglobin (abbreviated as HB in FIG. 2) concentration in an individual unknown sample.
  • a blood sample of unknown hematocrit or hemoglobin concentration, step 129 is observed by viewing the blood in an extracorporeal blood loop or in the organism, and the near infrared spectrum of this sample is detected or measured, step 130.
  • the second derivative intensity for the best wavelength determined in step 127 is computed for the unknown sample, step 131. Then the regression coefficients contained in the mathematical correlation, determined during the training procedure and saved in step 128, are applied to the second derivative wavelength obtained for the additional individual unknown blood sample 132, in order to yield the predicted hematocrit or hemoglobin concentration, step 133.
  • the pre-processing technique of multiple derivative transformation serves to eliminate the variances of spectral data caused by scatter in each of the various samples of both the training set and each unknown sample. This scatter would otherwise disrupt the accuracy of the detection of the training set spectra and its ability to predict the property of the unknown sample.
  • the second derivative transformation provides N spectral features less the loss of the features at the edges of the spectrum. In FIG. 2, such computation is shown at step 124.
  • the best wavelength must be chosen from the myriad of N transformed wavelengths using regression mathematical techniques, as is shown in FIG. 2 at step 125, depicted in a correlation plot at step 126, and selected at step 127 for use to determine the best possible regression coefficients in step 129 and for use with each unknown sample in step 132.
  • regression techniques such as, linear regression, multiple linear regression, stepwise regression, partial least squares regression, or principal component regression can be used to develop a statistical correlation between the ratio spectral features and the variable of the property being quantified.
  • regression techniques are available by reference to such literature as Draper and Smith, Applied Regression Analysis , Wiley and Sons, New York, 1982 and Geladi and Kowalski, Analytica Chimica Acta , Volume 185, pp 1-17 and 19-32, 1986.
  • regression models are computed against all of the possible N transformed wavelengths.
  • Each regression model is evaluated by using an accepted statistical measure.
  • one useful measure is the simple correlation coefficient computed from the actual hematocrit value obtained from the independent quantification and the predicted hematocrit value obtained from the regression model, as is shown in FIG. 2 at step 127.
  • a correlation plot can be constructed to visually show which wavelength involving the absorbance of water provides the highest correlation, as is shown in FIG. 2 at step 127.
  • a representative correlation plot for hemoglobin appears as FIG. 6. It is important to consider both high correlation and also the sensitivity of the correlation obtained to measure small changes in the actual wavelengths.
  • FIG. 3 is a schematic flow chart of the method of the present invention using for pre-processing the ratio pre-processing technique described herein and also disclosed in U.S. Patent Application Serial Number 07/408,746, which pre-processing is employed to minimize sample and instrumentation variability.
  • the regression analysis of the method identifies the nature of the mathematical correlation between the property to be analyzed in the first compartment and the water content in the biological matter, in order to predict the property to be analyzed in an unknown sample.
  • steps 220 to 228 which comprise the training phase of the analysis
  • steps 229 to 233 which comprise the prediction of the property of an unknown sample.
  • the training or calibration development phase consists of observing a series of blood samples 220 by diverting the samples of one or more animals of the same species through a blood loop or by otherwise observing the samples in the organisms. Additionally, for the independent quantification of property of interest, samples are obtained by withdrawing blood, step 221, from each of the animals participating in step 220.
  • steps 220 and 221 are analyzed on two parallel paths.
  • the first path consists of independent quantification of the property of interest, step 222. It is important that the independent quantification be done accurately.
  • the accuracy of the method of the present invention is dependent upon the accuracy of the independent quantification step 222 because validation of the mathematical correlation is based on the independently quantified value of the property of interest.
  • the second path consists of irradiating the samples with infrared light and detecting the near infrared spectrum for each sample, step 223, and then computing all possible ratios of two wavelengths in the spectrum, step 224.
  • the near infrared spectrum from 680 to 1235 nanometers consists of 700 individual absorbance measurements.
  • the preprocessing step of computing all possible ratios of two wavelengths expands the 700 point spectrum into 700 * 700 or 490,000 ratio pairs. Since near infrared spectra consist of broad, slowly changing absorbance bands, computing the ratio terms using every fifth data point, 140 point spectrum, results in equivalent performance with a significant decrease in the overall computation requirement, 140 * 140 or 19,600 ratio terms.
  • the preprocessed spectra for the set of training samples consisting of the calculated ratios, step 224, are correlated with the values obtained during the independent quantification step 222 by using a mathematical regression technique, step 225, such as linear regression.
  • the pair providing the best correlation of calculated values to actual values is generally the pair of wavelengths chosen for the ratio in the mathematical correlation.
  • One of the outputs of this regression step is a correlation map, step 226, which graphically shows the regions of the spectrum where the most useful ratio pairs are found.
  • the best ratio pair, step 227 is selected by identifying a region of high correlation which is also independent of small changes in the actual wavelength selected.
  • the regression coefficients corresponding to the selected ratio pair are saved, step 228, for future application to the analysis of individual samples of unknown analyte content.
  • the steps 229 to 233 in FIG. 3 show the procedure to be followed for predicting hematocrit (abbreviated as HCT in FIG. 3) or hemoglobin (abbreviated as HB in FIG. 3) concentration in an individual unknown sample.
  • a blood sample of unknown hematocrit or hemoglobin concentration, step 229 is observed in a dynamic condition and the near infrared spectrum of this sample is detected or measured, step 230.
  • the ratio of the absorbance readings for the selected pair of wavelengths determined in step 227 is computed for the unknown sample, step 231. Then the regression coefficients contained in the mathematical correlation, determined during the training procedure and saved in step 228, are applied to the ratio obtained for the additional individual unknown blood sample 232, in order to yield the predicted hematocrit or hemoglobin concentration, step 233.
  • the ratio pre-processing technique serves to eliminate the variances of spectral data caused by scatter or other multiplicative errors in each of the various samples of both the training set and each unknown sample. This scatter would otherwise disrupt the accuracy of the detection of the training set spectra and its ability to predict the property in the unknown sample. Because both wavelengths in the selected best pair of wavelengths used in the ratio experience the same path length, variations in the effective path length due to scatter are minimized.
  • the near infrared spectrum consists of N individual wavelengths
  • computing all possible ratios of each pair of wavelengths provides N*N new spectral features.
  • FIG. 3 such computation of all possible ratios is shown at step 224.
  • the best possible ratio pair of wavelengths must be distilled from the myriad of combinations using regression mathematical techniques, as is shown in FIG. 3, at step 225, depicted in a correlation map at step 226, and selected at step 227 for the use to determine the best possible regression coefficients in step 228 and for use with each unknown sample in step 231.
  • regression techniques such as, linear regression, multiple linear regression, stepwise regression, partial least squares regression, or principal component regression can be used to develop a statistical correlation between the ratio spectral features and the variable of the analyte being quantified.
  • regression techniques are available by reference to such literature as Draper and Smith and Geladi and Kowalski publications described above for use in multiple derivative transformation. In order to determine the best ratio for a given application, regression models are computed against all possible ratio pairs of wavelengths.
  • Each regression model is evaluated by using an accepted statistical measure.
  • one useful measure is the simple correlation coefficient computed from the actual hematocrit value obtained from the independent quantification and the predicted hematocrit value obtained from the regression model, as is shown in FIG. 3 at step 228.
  • a correlation map can be constructed to visually show which wavelength ratios provide the highest correlation, as is shown in FIG. 3, at step 226.
  • a representative correlation map for hemoglobin appears as FIG. 7. It is important to consider both high correlation and also the sensitivity of the correlation obtained to measure small changes in the actual wavelengths. The best overall ratio is found by selecting the pair of wavelengths which provide high correlation and which occur in a reasonably flat region of the correlation map.
  • the mathematical correlation endeavors to yield a linear relationship between the single independent variable, which is the multiple derivative transformed intensity or the ratio of the two best absorbance pairs, and the property of interest to be measured.
  • the linear functional relationship is more complex and involves more than one independent variable when the effect of oxygen saturation is used to adjust the mathematical correlation of hematocrit or hemoglobin concentration to the water content in whole blood.
  • the mathematical correlation is established, it is validated.
  • the accuracy in formation and performance is reviewed to assure reproducibility.
  • the accuracy and precision of the mathematical correlation can be validated by physical interpretation of the selected spectral features or using additional samples analyzed by independent quantification, step 122 of FIG. 2 or step 222 of FIG. 3, and then subjecting those samples to steps 129-133 of FIG. 2 or steps 229-233 of FIG. 3, as if the samples were unknown.
  • Statistical methods may then be used to compare the value of the predicted property, step 133 or step 233, and the value determined by independent quantification, step 122 or step 222, to confirm reproducibility.
  • Standard error of calibration measures precision of formation of the model of the training set spectra, i.e., how well the regression analysis performs with the data used to construct the training set.
  • the standard error of calibration can be calculated from the following equation: where N is the number of training samples, n is the number of absorbance terms in the regression technique employed, where c i is the hematocrit value of the ith sample as calculated during linear regression and C i is the hematocrit value of the ith sample as independently determined. The smaller the SEC, the more precise the model mathematical correlation has been formed.
  • the standard error of prediction measures the assurance of reproducible performance, i.e., a test to identify quantitatively the accuracy and precision of the prediction results obtained using the method of the present invention with the actual value for the property determined by independent quantification using known and accepted techniques and may be used in conjunction with a confidence limit to quantitatively express the accuracy of the prediction of the property being analyzed.
  • the standard error of prediction can be calculated from the following equation: where N is the number of validation samples, C i is the independently quantified value for the ith validation sample, c i is the value for the ith validation sample obtained using the mathematical correlation of step 131. Also, the smaller the SEP, the more accurate and precise the prediction.
  • Bias measures the extent of deviation of all points within a given data set in the solved mathematical equation from the line of exact correlation between predicted and actual values.
  • a low bias indicates the presence of a robustness of the training set spectra to tolerate possible error.
  • the robustness of the training set sampling anticipates the variety of sampling possibilities for the unknown sample and minimizes its effect.
  • the regression analysis may employ multiple variables according to the equations described above.
  • One multiple variable of assistance to the prediction of the property of interest is the percentage oxygen in the hemoglobin of whole blood, which distinguishes the hemoglobin between its oxy and deoxy forms. Because oxy and deoxy hemoglobin have different spectra, including in the region of 1150-1190 nm, the assessment of the relative contributions of both forms of hemoglobin, or a value proportional to their relative contributions, allows the adjustment of the mathematical correlation being developed for the prediction of hematocrit or hemoglobin concentration.
  • FIGS. 10 and 11 depict the schematic flow charts, similar to FIGS. 2 and 3, respectively.
  • Reference numbers 320-333 in FIG. 10 depicts the same steps as reference numbers 120-133 in FIG. 2.
  • Reference numbers 420-433 in FIG. 11 depicts the same steps as reference numbers 220-233 in FIG. 3.
  • FIGS. 10 and 11 add the steps in the method to adjust the mathematical correlation and the prediction to account for percent oxygen saturation in the whole blood.
  • measurement of oxygen saturation or a value proportional to oxygen saturation is added to assist in performing the linear regression, step 325, and step 330 is modified to include the measurement of the oxygen saturation or a value proportional to oxygen saturation in the unknown sample.
  • step 434 is added to assist in performing the linear regression, step 425, and step 430 is modified to include the measurement of the oxygen saturation or a value proportional to oxygen saturation in the unknown sample.
  • step 434 provides the adjustment of the independent variable, percent oxygen saturation or a value proportional to oxygen saturation, to the other independent variable, the multiple derivative transformed spectral intensity at the best wavelength or the best ratio.
  • the use of the percent oxygen saturation independent variable in the mathematical correlation is optional.
  • the use of the percent oxygen saturation independent variable in the mathematical correlation is preferred.
  • Instruments to measure oxygen saturation of the hemoglobin concentration at the same time as the spectrum of whole blood is analyzed includes such commercially available instrumentation as a co-oximeter, a pulse oximeter, or other device which measures the oxygen saturation known to those skilled in the art.
  • Co-oximetry typically involves measurement of oxygen saturation in a static condition.
  • the art has progressed to measuring oxygen saturation in flowing blood such as that shown in U.S. Patent 4,745,279.
  • Another method of measuring the second independent variable as a value proportional to percent oxygen saturation for purposes of the regression analysis depicted in FIG. 10 at 334 and 330, respectively and FIG. 11 at 434 and 430, respectively, is to employ a ratio of absorbances at two wavelengths.
  • the value proportional to percent oxygen saturation is the ratio of the absorbances of two wavelengths where the ratio of the extinction coefficients for oxyhemoglobin and deoxyhemoglobin at one wavelength is different than that ratio at the second wavelength.
  • the ratio uses the absorbance of a wavelength where the extinction coefficients of oxy and deoxy hemoglobin are different, (for example at from about 680 nm to 720 nm), to the absorbance of a wavelength where the extinction coefficients of oxy and deoxy hemoglobins are the same, the isosbestic point.
  • Use of the ratio of this spectral data obviates the need for additional oxygen saturation instrumentation.
  • the comparison of predicted vs. actual hematocrit or hemoglobin concentration may be graphed when the percent oxygen saturation is included as an independent variable.
  • FIG. 12 shows a graph of predicted hematocrit against actual hematocrit.
  • a comparison of FIG. 8 and FIG. 12 shows how the multiple independent variable mathematical correlation is generally more accurate.
  • An embodiment of the analysis of a property of interest in a biological fluid in a dynamic condition employs an extracorporeal blood loop.
  • This blood loop permits "real time” monitoring of the changes in the values of the property of interest in whole blood.
  • FIG. 14 identifies schematically the type of blood loop of the present invention using reference numerals while the other equipment necessary for the experiments described in the examples are identified by reference letters.
  • the loop 500 is formed by connecting flow through cell 510 in the spectrometer S, also seen in FIG. 1 as item 113, tubing, generally 520, and valves, generally 530.
  • the loop 500 may be separately configured to the patient P or may form a subloop to the loop already established for the patient P in the operative environment.
  • Loop 500 includes the following components interconnected: diversion section tubing 521 connected between the patient's blood vessel (not shown) and valve 532, diversion section tubing 522 between the valve 532 and flow through cell 510, return section tubing 523 between the flow through cell 510 and valve 534, return section tubing 524 between valves 534 and 536, return section tubing 525 between valve 536 and another blood vessel (not shown) of the patient P, and a bypass tubing section 526 between valves 532 and 536.
  • the tubing, generally 520, and the valves, generally 530, must be made from materials which are biocompatible with the patient's biological fluid and strong enough to withstand use of flowing pressurized fluid therethrough. A leak in the loop 500 could be traumatic for the patient P.
  • tubing 520 Preferred commercially available materials for the tubing 520 are "TYGON" brand plastic tubing available from Norton Performance Plactics of Akron, Ohio.
  • Preferred commercially available valves are three-way stopcock type valves marketed under the trademark "INTRALOK” from Abbott Sorenson Research of Salt Lake City, Utah.
  • the flow through cell 510 must be made of a transparent material used in spectrophotometric instrumentation, such as quartz plate glass, and geometrically configured and constructed in a manner to minimize the stagnation of the biological fluid in that portion of the cell irradiated with the near infrared light. Glassblowers skilled in the art are capable of configuring the cell 510, which preferably has an oval shape with opposing ports at the perimeters of sharper curvatures.
  • the loop 500 has a biological fluid flow in the direction of arrow F1 from the patient P through diversion section comprising tubing 521 and 522 and in the direction of arrow F2 to the patient through tubing 523, 524, and 525.
  • valves 532 and 536 allow the control of the amount of biological fluid flowing through cell 510. It is desired that adequate biological fluid flow through cell 510 during spectral detection. However, if it is desired to entirely bypass cell 510, valves 532 and 536 may be opened in a way to direct all fluid flow through section 526.
  • Valve 534 is adjacent the emergence of the tubing 523 from the cell 510 in order that any independent quantification needed or desired may be performed in the loop as closely as possible to the location of the spectral irradiation and detection in the cell 510.
  • loop 500 may be combined with any spectrometric instrumentation described above, although the use of a spectrometer such as a Model 6250 spectrometer, with a computer such as a personal computer, described above is preferred.
  • a spectrometer such as a Model 6250 spectrometer
  • a computer such as a personal computer
  • spectra data may be gathered in conjunction with an extracorporeal blood gas sensor (EBGS) sold by Cardiovascular Devices, Inc. of Irvine, California.
  • EBGS extracorporeal blood gas sensor
  • hematocrit or hemoglobin concentration may be monitored nearly instantaneously, permitting the health care practitioner to treat the patient without delay.
  • the extracorporeal loop 500 may be used in routine dialysis procedures as part of the dialysis blood loop to monitor the water content of the blood and other properties of interest. Another use of the extracorporeal loop 500 is in critical cases of prematurely born babies, neonatals, that require the use of ExtraCorporeal Membrane Oxygenators (ECMO) wherein a blood loop is formed with the ECMO to oxygenate the blood for days, if needed, until the proper maturation of lung functions is attained. It is a critical setting, and continuous monitoring of the blood components such as hemoglobin concentration and hematocrit among other properties, can be vital. Further, the use of loop 500 in the ECMO eliminates the undesirable need to withdraw blood samples for these analyses from the neonatal infant already in critical condition.
  • ECMO ExtraCorporeal Membrane Oxygenators
  • a flow through cell 510 or an extracorporeal blood gas sensor with a cell 510 permits real time monitoring of the time taken to commence and complete the oxygenation change as well as maintaining in real time a monitor of the patient's condition for properties of interest such as hematocrit, hemoglobin concentration, and percent oxygen saturation.
  • the spectra set A was gathered using a 11 Kg female Beagle dog approximately two years old; and the spectra set B was gathered using a 11 Kg. female Beagle dog approximately four and one half years old. While there were some minor variations during the experimentation, the experiments used the following protocol with the following materials, instruments, and supplies.
  • the method of the experiment was as follows: the Beagle dog was first administered by subcutaneous injection 0.05 mg/Kg of the sedative Acepromazine and then 0.025 mg/Kg of Atropine. Anaesthesia was induced by the administration of the barbituate Bio-tal (4%) to obtain the desired level of anaesthesia which was then sustained by the intubation of the trachea and maintained with a mixture of isoflurane in pure oxygen from the respirator, R.
  • the skin was shaved on the medial aspects of the hind legs and the neck for placement of the cannulae and the animal was transferred from initial preparation areas to the operating room.
  • a jugular vein cut-down at the shaved neck area was performed and the teflon cannula was inserted and connected to a drip bag containing the lactated Ringers Solution, L, dripping at the rate of 2 to 5 ml per pound per hour.
  • the anaesthesia was maintained by continued delivery of isoflurane at 1-2 percent delivered in pure oxygen via the semi-open anaesthesia system.
  • Three EKG electrodes were attached on the thorax of the animal at appropriate diagnostic locations and connected via cables to the Burdick CS525 EKG-Blood Pressure Monitor, M.
  • Electro-surgical plate (not shown in FIG. 12) was placed under the animal on the back with an electrically conductive paste (Gel #1103 available from Minnesota Mining and Manufacturing Company) between the plate and the skin.
  • An electro-surgical scalpel (not shown in FIG. 12) was attached to an electro-surgical unit (ESU) generator, ES, and used to make a skin incision over the proximal medial femur with dissection carried down to expose the femoral artery and vein.
  • ESU electro-surgical unit
  • ES electro-surgical unit
  • Fourteen gauge “TEFLONTM" cannulae were inserted into the femoral artery and vein, respectively, and tied in place with a 2-0 vinyl suture.
  • the contra-lateral femoral artery similarly exposed and a 14 gauge cannulae was inserted and similarly secured with suture.
  • This latter cannulae was connected to the Burdick Corporation blood pressure transducer, M, and connected via hydraulic lines to a pressurized bag containing 0.9 percent sodium chloride solution dripping at approximately 3 ml per hour to prevent any clogging of the cannula.
  • the thermometer readings were displayed on the "YSI-400" Readout Temperature Monitor, T.
  • a second channel of that monitor was connected to a thermometer needle inserted into the tubing section 523 at the outlet port of the blood flow through cell 510 to monitor the temperature of the blood in the extracorporeal loop 500.
  • the "TYGON R " tubing was assembled in lengths from about 30 cm to 50 cm.
  • One stop cock valve, 532 was placed in the diversion section of the loop between tubing 521 and 522.
  • a second stop cock valve, 536 was placed in the return section of the loop between tubing 524 and 525. Between the two valves, 532 and 536, a piece of tubing 526 was connected to provide a bypass, which by manipulation of the two valves, 532 and 536, could eliminate flow of the blood through the flow through cell 510 entirely, or to control the rate of flow therethrough.
  • a third stopcock valve, 534 was placed in the return section of the extracorporeal blood loop 500 between tubing 523 and 524 to permit withdrawal of samples periodically for testing of various blood related parameters using the centrifuge, MC, the co-oximeter, O, the blood gas analyzer, BG, and the glucose test strips.
  • the flow through cell 510 was connected to the opposing ends of the diversion section at tubing 522 and the return section at tubing 523 and placed within the Model 6250 Spectrometer.
  • the cell 510 and associated tubing 520 was filled with a 0.9% NaCl solution made by Abbott Laboratories of North Chicago, Illinois in order to remove air from the cell 510 and tubing 520 to avoid injection of air emboli upon connection of the extracorporeal loop 500 to the animal and to allow recording of a spectra of water so that known features of the water may serve as a reference of the proper functioning of the loop 500 and spectrophotometric system depicted in FIG. 1.
  • the flow through cell 510 was approximately 6 cm long and 3.5 cm wide at the middle of the cell and mounted onto a transport metal plate of the dimensions of 11 cm by 6 cm with a circular aperture of approximately 1.5 cm. The plate was inserted into the positioning tracks of the chamber and the Model 6250 Spectrometer, S. The chamber cover was shut and taped to prevent accidental opening during the experiment.
  • the computer control of the cell transport mechanism was disabled by disconnecting the transport board cable between the PS/2 Personal Computer, C and the Model 6250 Spectrometer, S. This was done to prevent movement of the cell 510.
  • the tubing 522 of the loop 500 leading to and the tubing 523 coming from the Model 6250 Spectrometer, S was wrapped with black vinyl electrical tape available from Minnesota Mining and Manufacturing Company.
  • the tubing itself was prevented from acting as a light guide which upon entering the cell would serve as a noise source of light.
  • the animal was injected with 3800 units of sodium heparin from a 1,000 unit/ml solution available under the brand name "LYPHOMED".
  • the heparin served as a blood anticoagulant because the blood in the extracorporeal loop would be in contact with various materials such as the "TEFLONTM” cannulae, valves 530, tubing 520, and the flow through cell 510.
  • the diversion section tubing 522 was connected to the inlet port of the cell 510 so that any spurious air bubbles would be flushed from the cell 510.
  • the extracorporeal loop 500 was adjusted at valves 532 and 536 to permit the animal's blood to flow from the animal through the flow through cell 510 and back to the animal, avoiding the bypass tubing 526 between the diversion section valve 532 and the return section 536 which would eliminate blood flow through the flow through cell 510.
  • a 1 ml sample of blood in a 1 ml syringe was withdrawn through valve 534 and subjected to blood gas analysis and co-oximetry and centrifuging. Less than 10 seconds after the withdrawal of the blood sample, 64 scans of spectra were acquired by the spectrometer upon initiation from the personal computer. Approximately 24 seconds were required to obtain these spectra.
  • valve 534 Strict adherence to the protocol of blood sample handling is required to minimize aberrations. For example, blood is withdrawn into new syringes for every sample. The operation of the valve 534 where the blood is withdrawn must be such that only blood exiting the flow through cell 510 fills the syringe in order to avoid any blood which has proceeded further in the direction of the return to the animal has not been also withdrawn. A first one-third to one-half ml of withdrawn blood is reinjected into valve 534 positioned to direct such reinjected blood into section 524 and towards the animal. This procedure helps to force any old blood and/or air in the valve from being also withdrawn.
  • the next one ml of blood withdrawn in the syringe is removed for analysis by instruments, O, MC, and BG. Further, the blood from the syringe is injected into all three of the diagnostic analyzers, O, BG, and MC as soon as possible, within less than a minute, in order to obtain accurate readings not affected by atmospheric changes to the samples.
  • the blood gas analysis showed an oxygen saturation of 68.6 percent with a corresponding PO 2 of 27.8 mm of Hg.
  • the 64 spectra were recorded by the spectrometer, S, by initiation from the personal computer keyboard, C.
  • the 100 ml of blood withdrawn was centrifuged at 3000 RPM for 10 minutes in 2 centrifuge tubes of equal volumes and weights in a "BECKMAN GPR" refrigerated centrifuge, RC, utilizing a "GH-3.7" rotor available as catalog #349702 from Beckman Instrument, Inc. of Palo Alto, California.
  • the plasma supernatent fraction was removed with a pipette from each tube and the densely packed red blood cells in the lower portion of the centrifuge tubes were stored in the refrigerator at approximately 4°C.
  • the plasma was returned to the animal through the same valve 534 to maintain plasma volume but with a reduced hematocrit and hemoglobin concentration.
  • the procedure of withdrawing 100 ml of blood, centrifuging it, re-injecting the plasma and storing the red blood cells in the refrigerator was repeated several times. Each time, the blood gas analysis was performed and the spectra taken both before and after each such procedure.
  • the hematocrit varied for each animal, e.g. for one animal from an initial percent of about 47 percent to a low of about 22 percent, at which point the refrigerated red blood cells were re-injected into the animal through the valve in the return section of the loop to increase the hematocrit to its original level and to restore the hemoglobin concentration.
  • Spectra were taken before and after the red blood cell re-injection into the loop and contributed to the spectra used for the training set spectra from which the mathematical regression techniques after pre-processing established the mathematical correlation between the hemoglobin concentration or hematocrit and the water content of the blood.
  • Table I identifies the sessions as sets A and B, and the number of samples analyzed are identified as the number of spectra obtained, which varied as shown.
  • a representative group of samples from set A are graphed in FIG. 4.
  • the sample spectra indicated the ranges of variability of the spectral data found, against which mathematical correlations would have been otherwise attempted to be calculated.
  • Hct hematocrit
  • Hb hemoglobin concentration
  • O 2 Sat. percent oxygen saturation range
  • Table I below further identifies the correlation of hematocrit to hemoglobin which demonstrated correlation for the spectra observed greater than 0.99 for both sets.
  • Sets of Samples Spectrally Analyzed and Independent Quantification Ranges of Hematocrit, Hemoglobin and Oxygen Saturation Set No. of Spectra Hct Range (%) Hb Range (g/dL) Hct/Hb Corr. O 2 Sat. Range (%) A 19 22-47 8.0-16.6 0.999 67.0-100.3 A1 14 22-47 8.2-10.7 99.2-100.3 B 8 24-32 8.2-10.8 0.995 61.2- 99.8 B1 6 24-31 8.0-10.7 98.5- 99.8
  • the purpose of establishing a training set for comparisons and prediction purposes is to attempt to anticipate sampling differences which may exist in various individuals at various times.
  • the training set should be as broad as possible to include as many variances within each of the factors affecting the measurement of the property of interest.
  • the training set includes samples that represent all of the different kinds of changes in the hematocrit and hemoglobin concentration over a full range of values likely to be encountered in an unknown sample as well as all of the other kinds of changes within each factor likely to affect blood sampling, e.g., temperature, amount of liquids, details of light scattering, presence of other components, and physiological condition of the patient.
  • the second derivative pre-processing technique was performed against the combination of the sets using the Near Infrared Spectral Analysis software program described above, with a personal computer described above, and available with the Model 6250 spectrometer from Near Infrared Systems to compute the second derivatives, to perform the linear regression, to select the best wavelength, and to save the regression coefficients (steps 124, 125, 127, 128, and 131 of FIG. 2).
  • Other software "VAX IDL Interactive Data Language” available from Research Systems, Inc. (copyright 1982-1988) was used to apply the regression model, predict the property, (steps 132 and 133 of FIG. 2) and to compute the SEC, SEP, and the bias for validation purposes.
  • the group of spectra for Set A are shown in FIG. 4 are re-depicted in FIG. 5 after the second derivative pre-processing has been performed.
  • the variations in absorbances as caused by baseline offsets and other variances from spectrum to spectrum are minimized, permitting better attempted mathematical correlation.
  • the second derivative pre-processing technique computes a transformed absorbance value for all of the wavelengths in order to find the best correlation in the area of the water absorbance peak.
  • Another reason for rejection of a wavelength in the 900 nm region of broad hemoglobin absorbance is the possible interference by other forms of hemoglobin absorbing in this region, such as methemoglobin.
  • FIG. 6 depicts that correlation plot.
  • the correlation in the region of 890 nm is an anomalously sharp band where variations in the wavelength selected can significantly reduce the extent of correlation.
  • the correlation in the region of 1150 to 1190 nm is a broader band where variations in the wavelength selected do no significantly reduce the extent of correlation. As discussed below, predictions using a wavelength within this range are acceptable.
  • Example 1 The validation of the performance of the selected linear functional equation described in Example 1 was performed to assess standard error of prediction (SEP) and bias. Each set was used as a known and used to predict each other set as if such other set were unknown.
  • SEP standard error of prediction
  • VAX IDL software The Near Infrared Spectral Analysis software and the VAX IDL software were used in the same manner as described in Example 1 and used in Example 2 to compute the results. Table III shows the results found.
  • Segregated sets A1 and B1 provided the more precise predictions, but the larger set A having a better balance of percent oxygen saturation spectra variations predicted set B1 with acceptable precision.
  • the prediction by set B and the prediction of set B showed the effects that two outlier spectra can have on a smaller set having less robustness of spectra.
  • Bias for the predictions by all of the sets were more positive when predicting the segregated sets A1 or B1 than when predicting the full sets A or B, again indicating an under-prediction is possible when the spectra has a lower percent oxygen saturation.
  • FIG. 8 is a graph of the comparison of predictions of set A to the actual independently quantified values for hematocrit.
  • the percent oxygen saturation of the patient was added as an independent variable to the linear functional equation and multiple linear regression analysis or the like was performed as depicted in FIG. 10 in the case of multiple derivative transformation pre-processing.
  • the percent oxygen saturation was measured for each spectrum using the "IL-482" co-oximeter. That data comprised one column of data used in replacement of one column of spectral data to achieve a multiple variable set of data, which the Near Infrared Spectral Analysis software and the VAX IDL software computed in the manner described in Examples 1-3 to yield the mathematical results.
  • Table VI shows the results found when individual sets were used to predict other individual sets for hemoglobin where the percent oxygen saturation was added to the mathematical analysis as an independent variable.
  • Table VII shows the analogous results for hematocrit. Prediction of Individual Sets against Other Individual Sets With Adjustment For Percent Oxygen Saturation From A Co-Oximeter For Hemoglobin at 1170 nm After Second Derivative Pre-Processing Known Set R SEC g/dL O 2 Slope Slope Intercept Unknown Set SEP g/dL Bias g/dL A 0.996 0.27 -0.109 159.01 11.00 B1 0.76 -0.51 B 0.62 -0.32 B 0.999 0.16 -0.083 147.63 9.59 A1 0.49 0.28 A 0.46 0.15 Prediction of Individual Sets against Other Individual Sets With Adjustment For Percent Oxygen Saturation From A Co-Oximeter For Hematocrit at 1169 nm After Second Derivative Pre-Process
  • FIG. 12 shows the high resolution of accuracy between the method used in this Example 5 and the independent quantification used for the same spectra and how that resolution is more accurate than that shown in FIG. 8.
  • the effect of variations in percent oxygen saturation among the spectra was also calculated from the spectra without use of the co-oximeter.
  • the ratio of the wavelengths of 700 and 820 nm, was proportional to the percent oxygen saturation which existed in each sample as it was analyzed. That ratio data from the originally detected spectra replaced one column of transformed spectral data to achieve a multiple variable set of data, which the Near Infrared Spectral Analysis software and the VAX IDL software computed in the manner described in Examples 1-3 to yield the mathematical results.
  • Table VIII shows the results found for hemoglobin when the adjustment for percent oxygen saturation was determined by the ratio described here.
  • Table IX shows the analogous results found for hematocrit.
  • ratio pre-processing technique provided comparable results to the use of the multiple derivative pre-processing technique.
  • the ratio pre-processing method depicted in FIG. 3 was employed using the following Fortran generated software program described herein, with a personal computer, to select the best ratio, to perform the linear regression, and to save the regression coefficients (steps 224, 225, 227, and 228 of FIG. 3).
  • Procedures in the VAX IDL Interactive Data Language software program described in Example 1 were used to perform the ratio pre-processing on the unknown sample, apply the regression model and predict the property, (steps 231, 232, and 233 of FIG. 3) and to compute the SEC, SEP, and bias for validation purposes.
  • the ratio pre-processing technique computed substantially possible wavelength pairs, as described above, in order to find the best correlation in the area of the water absorbance peak and another absorbance measuring point.
  • Table X shows the results found using this equation as applied to predict each set A1, A, B1, and B against the combined set A + B for hemoglobin concentration. Prediction of Individual Sets against Combined Set For Hemoglobin at Ratio of 820/1161 nm Set R SEC g/dL Bias g/dL A1 0.998 0.32 -0.16 A 0.992 0.39 0.00 B1 0.994 0.36 -0.22 B 0.832 0.92 0.14
  • the results provide proof of the accuracy and the precision of the linear functional equation for predicting hemoglobin in a dynamic condition of an extracorporeal blood loop of a mammal. Recognizing the effects of outlier spectra in set B as previously described in a smaller set than that to be used in forming the training set, the most precise predictions arise from segregated sets A1 and B1, followed by the predictions of and with set A. The trend in the bias is slightly toward the positive, but all sets were predicting within a range of acceptable bias.
  • Example 7 The same experiments as those described in Example 7 were conducted for the analysis of hematocrit using the ratio pre-processing technique computed using the same software and procedures as described in Example 7.
  • the combined sets A and B were analyzed for the best wavelength pair not likely to be rendered inaccurate by changes in concentration of the various forms of hemoglobin, i.e., in the range of 1150-1190 nm and around the isosbestic point.
  • Bias for the predictions by all of the sets were more negative when predicting the segregated sets A1 or B1 than when predicting the full sets A or B, indicating a possible over-prediction is possible when the spectra has a lower percent oxygen saturation. But the bias in all sets' predictions is acceptable.
  • FIG. 9 is a graph of the comparison of predictions of set A to the actual independently quantified values for hematocrit.
  • FIG. 11 depicts the method of the invention altered to adjust for the use of the second independent variable.
  • the 820/1161 nm ratio computed with the VAX IDL software was added with the co-oximeter measurements to produce a linear summation, and then computed with a multiple linear regression analysis procedure of the VAX IDL software to yield the mathematical results.
  • Tables XIV and XV show the results found when including the co-oximeter measurements of percent oxygen saturation into the equation for hemoglobin and hematocrit, respectively.
  • FIG. 13 shows the high resolution of accuracy between the method used in this Example 9 and the independent quantification used for the same spectra and how that resolution is more accurate than that shown in FIG. 9.
  • the effect of variations in percent oxygen saturation among the spectra was also calculated from the spectra without use of the co-oximeter.
  • the ratio of the absorbances at the wavelengths of 700 and 820 nm was proportional to the percent oxygen saturation existing in each sample as it was analyzed.
  • the 820/1161 nm ratio computed with the VAX IDL software was added with the 700/820 nm ratio to produce a linear summation, and then computed with a multiple linear regression analysis procedure of the VAX IDL software to yield the mathematical results.
  • Table XVI shows the results found for hemoglobin when the adjustment for percent oxygen saturation was determined by the ratio described here.
  • Table XVII shows the analogous results found for hematocrit.

Claims (10)

  1. Procédé pour analyser une propriété d'une substance biologique ayant une teneur en eau dans une condition dynamique, la substance biologique étant rapprochée pour comprendre un premier compartiment en relation avec la propriété qui doit être analysée et un second compartiment contenant une quantité d'eau proportionnellement plus grande ou plus petite que le premier compartiment, le procédé comprenant :
    (a) l'observation d'échantillons multiples de la substance biologique dans une condition dynamique ;
    (b) l'irradiation avec une lumière infrarouge proche desdits échantillons multiples de la substance biologique ;
    (c) la détection du spectre d'absorption infrarouge proche de chacun desdits échantillons multiples sous forme de données spectrales se composant de mesures d'absorbance ;
    (d) l'application, à titre de prétraitement, d'une technique de rapport aux données spectrales des mesures d'absorbance du spectre de chacun desdits échantillons multiples pour identifier une multiplicité de paires de longueurs d'ondes en rapport ;
    (e) la quantification indépendante de la propriété qui doit être analysée pour chacun desdits échantillons multiples ;
    (f) l'établissement d'un jeu d'apprentissage à partir desdits spectres d'absorption infrarouge proche de l'étape (d) desdits échantillons multiples en utilisant la multiplicité de paires de longueurs d'ondes en rapport ; et
    (g) l'identification par une méthode statistique de la nature d'une meilleure corrélation mathématique des deux compartiments entre la propriété qui doit être analysée dans le premier compartiment et la teneur en eau dans la substance biologique (1) en corrélant les valeurs obtenues durant l'étape (e) avec les valeurs obtenues durant l'étape (f) et (2) en sélectionnant une paire de longueurs d'ondes en rapport parmi les mesures d'absorbance, dans laquelle une des longueurs d'ondes est un fort pic d'absorbance de longueur d'onde infrarouge proche de la teneur en eau et dans laquelle la seconde longueur d'onde de la paire de longueurs d'ondes en rapport est un autre point de mesure d'absorbance d'une longueur d'onde infrarouge proche ayant des absorbances dans le premier compartiment, dans lequel la paire en rapport est choisie pour réduire la variabilité de la propriété qui doit être analysée.
  2. Procédé selon la revendication 1 comprenant, en outre, les étapes suivantes :
    (h) observation d'un échantillon inconnu de la matière biologique dans une condition dynamique ;
    (i) l'irradiation dudit échantillon inconnu avec une lumière infrarouge proche ;
    (j) la détection du spectre infrarouge proche dudit échantillon inconnu sous forme de données spectrales se composant de mesures d'absorbance ;
    (k) l'application, à titre de pré-traitement, de ladite technique de rapport en utilisant la paire de longueurs d'ondes en rapport sélectionnée dans l'étape (g) aux données spectrales des mesures d'absorbance dudit échantillon inconnu ; et
    (l) la prédiction de la propriété qui doit être analysée dans ledit échantillon inconnu en utilisant ladite meilleure corrélation des deux compartiments, obtenue dans ladite étape d'identification par une méthode statistique (g).
  3. Procédé selon la revendication 1 ou la revendication 2, dans lequel ladite corrélation mathématique dans ladite étape d'identification par une méthode statistique (g) comprend une fonction linéaire apparentée à un pic d'absorbance infrarouge proche de l'eau dans les spectres d'absorption desdits échantillons multiples soumis à ladite technique de pré-traitement.
  4. Procédé selon la revendication 1 ou la revendication 2, dans lequel la substance biologique est le sang total et la propriété du premier compartiment qui doit être analysée est l'hématocrite.
  5. Procédé selon la revendication 1 ou la revendication 2, dans lequel la substance biologique est le sang total et la propriété du premier compartiment qui doit être analysée est la concentration de l'hémoglobine dans le sang total.
  6. Procédé selon la revendication 4 ou la revendication 5, dans lequel la substance biologique est le sang total et ledit pic d'absorbance de l'eau se produit dans les spectres infrarouges proches entre environ 1150 et environ 1190 nanomètres.
  7. Procédé selon la revendication 4, la revendication 5, ou la revendication 6, dans lequel ledit autre point de mesure de l'absorbance des longueurs d'ondes infrarouges proches est le point isosbestique de l'oxyhémoglobine et de la désoxyhémoglobine.
  8. Procédé selon la revendication 1 comprenant, en outre, les étapes suivantes :
    (1) observation d'échantillons supplémentaires de la substance biologique dans une condition dynamique ;
    (2) quantification indépendante de la propriété qui doit être analysée pour chacun desdits échantillons supplémentaires ;
    (3) application des étapes (b), (c), et (d) auxdits échantillons supplémentaires ;
    (4) prédiction de la propriété qui doit être analysée dans chacun desdits échantillons supplémentaires en utilisant ladite corrélation mathématique obtenue dans ladite étape d'identification par une méthode statistique (g) ; et
    (5) validation de ladite corrélation mathématique en comparant la propriété prédite dans l'étape (4) à la propriété indépendamment quantifiée dans l'étape (2).
  9. Procédé selon l'une quelconque des revendications 2 à 7, dans lequel la substance biologique est le sang animal total et comprenant, en outre, les étapes de quantification indépendante d'une valeur proportionnelle à la saturation en oxygène, sous forme de pourcentage, dans le sang animal total pour chacun desdits échantillons multiples et la détermination d'une valeur proportionnelle à la saturation en oxygène, sous forme de pourcentage, de l'échantillon inconnu.
  10. Procédé destiné à surveiller une propriété d'intérêt dans le sang total d'un patient vivant, pratiquement simultanément avec la circulation du sang total dans le corps du patient, comprenant :
    (a) l'établissement d'une boucle de circulation sanguine ayant une section de détournement qui part du patient et aboutit à une cuve à circulation, une section de retour qui retourne vers le patient à partir d'une cuve à circulation, et une section de dérivation entre la section de détournement et la section de retour ;
    (b) la mise en circulation du sang total dans la boucle sanguine ;
    (c) l'utilisation de moyens de détection infrarouge proche pour surveiller la propriété d'intérêt dans le sang total circulant dans la boucle sanguine ; et
    (d) l'identification de la valeur de la propriété d'intérêt en utilisant une méthode de corrélation d'une relation fonctionnelle linéaire ;
       dans lequel ladite relation fonctionnelle linéaire est établie par le procédé selon l'une quelconque des revendications précédentes.
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DE69032339D1 (de) 1998-07-02
ES2118714T3 (es) 1998-10-01
EP0419223A2 (fr) 1991-03-27
DK0419223T3 (da) 1999-03-22
CA2025330A1 (fr) 1991-03-19
EP0419223A3 (en) 1992-05-20
US5830133A (en) 1998-11-03
CA2025330C (fr) 2002-01-22
US5729333A (en) 1998-03-17
JP3213308B2 (ja) 2001-10-02
DE69032339T2 (de) 1998-12-24
JPH03118446A (ja) 1991-05-21

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